Paul G. Wakim

Site Selection in Community-Based Clinical Trials for Substance Use Disorders: Strategies for Effective Site Selection

Background: The importance of conducting substance use disorder treatment research in real-world settings is now well recognized. While this approach to clinical trials research offers a variety of benefits, challenges also arise. Selecting high-quality sites to participate is critical to recruitment, retention, and overall trial performance when conducting multi-site, community-based clinical trials of treatments for substance use disorders. Objectives: Over the past 10 years, the National Institute on Drug Abuse-sponsored National Drug Abuse Treatment Clinical Trials Network (CTN) has strived to conduct high-quality, well-managed clinical trials. This includes developing methods for site selection to be used by investigators conducting CTN trials. Methods: We review site selection strategies from two community-based multi-site clinical trials conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network. Results: Issues relevant to site selection include the clinical trial design, availability of appropriate clinical population, and organizational attributes of potential clinical research sites. Site selection strategies include reviewing regional epidemiologic data, collecting standard site selection surveys, evaluating clinic data on existing patient populations, and site selection interviews and visits. Conclusion: This article describes considerations for selecting research sites and identifies specific strategies to employ when selecting community-based sites for participation in clinical trials.

Views of American OB/GYNs on the ethics of prenatal whole‐genome sequencing

Given public demand for genetic information, the potential to perform prenatal whole‐genome sequencing (PWGS) non‐invasively in the future, and decreasing costs of whole‐genome sequencing, it is likely that OB/GYN practice will include PWGS. The goal of this project was to explore OB/GYNs views on the ethical issues surrounding PWGS and their preparedness for counseling patients on its use.

Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels

OBJECTIVEnPremenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression and stimulated by administration of ovarian steroids, yet they appear with ovarian steroid levels indistinguishable from those in women without PMDD. Thus, symptoms could be precipitated either by an acute change in ovarian steroid levels or by stable levels above a critical threshold playing a permissive role in expression of an underlying infradian affective pacemaker. The authors attempted to determine which condition triggers PMDD symptoms.nnnMETHODnThe study included 22 women with PMDD, ages 30 to 50 years. Twelve women who experienced symptom remission after 2-3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received 1 month of single-blind (participant only) placebo and then 3 months of continuous combined estradiol/progesterone. Primary outcome measures were the Rating for Premenstrual Tension observer and self-ratings completed every 2 weeks during clinic visits. Multivariate repeated-measure ANOVA for mixed models was employed.nnnRESULTSnBoth self- and observer-rated scores on the Rating for Premenstrual Tension were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with the last month of leuprolide alone, the placebo month, and the second and third months of estradiol/progesterone. There were no significant differences in symptom severity between the last month of leuprolide alone, placebo month, or second and third months of estradiol/progesterone. Finally, the Rating for Premenstrual Tension scores in the second and third estradiol/progesterone months did not significantly differ.nnnCONCLUSIONSnThe findings demonstrate that the change in estradiol/progesterone levels from low to high, and not the steady-state level, was associated with onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

Treatment outcomes in opioid dependent patients with different buprenorphine/naloxone induction dosing patterns and trajectories

BACKGROUND AND OBJECTIVESnInduction is a crucial period of opioid addiction treatment. This study aimed to identify buprenorphine/naloxone (BUP) induction patterns and examine their association with outcomes (opioid use, retention, and related adverse events [AEs]).nnnMETHODSnThe secondary analysis of a study of opioid-dependent adults seeking treatment in eight treatment settings included 740 participants inducted on BUP with flexible dosing.nnnRESULTSnLatent class analysis models detected six distinctive induction trajectories: bup1-started and remained on low; bup2-started low, shifted slowly to moderate; bup3-started low, shifted quickly to moderate; bup4-started high, shifted to low; bup5-started and remained on moderate; bup6-started moderate, shifted to high dose (Fig. 1). Baseline characteristics, including Clinical Opioid Withdrawal Scale (COWS), were important predictors of retention. When controlled for the baseline characteristics, bup6 participants were three times less likely to drop out the first 7 days than bup1 participants (adjusted hazard ratio (aHR)u2009=u2009.28, pu2009=u2009.03). Opioid use and AEs were similar across trajectories. Participants on ≥16u2009mg BUP compared to those on <16u2009mg at Day 28 were less likely to drop out (aHRu2009=u2009.013, pu2009=u2009.001) and less likely to have AEs during the first 28 days (aORu2009=u2009.57, pu2009=u2009.03).nnnDISCUSSION AND CONCLUSIONSnBUP induction dosing was guided by an objective measure of opioid withdrawal. Participants with higher baseline COWS whose BUP doses were raised more quickly were less likely to drop out in the first 7 days than those whose doses were raised slower.nnnSCIENTIFIC SIGNIFICANCEnThis study supports the use of an objective measure of opioid withdrawal (COWS) during BUP induction to improve retention early in treatment.

Sex differences in visuospatial abilities persist during induced hypogonadism.

BACKGROUNDnDespite well-established sex differences in the performance on tests of several cognitive domains (e.g., visuospatial ability), few studies in humans have evaluated if these sex differences are evident both in the presence of circulating sex hormones and during sex steroid hormonal suppression. Sex differences identified in the relative absence of circulating levels of estradiol and testosterone suggest that differences in brain structure or function exist independent of current hormonal environment and are more likely a reflection of differing developmental exposures and/or genetic substrates.nnnOBJECTIVEnTo evaluate cognitive performance in healthy eugonadal men and women before and again during GnRH agonist-induced hypogonadism.nnnMETHODSnMen (n=16) and women (n=15) without medical or psychiatric illness were matched for IQ. Cognitive tests were performed at baseline (when eugonadal) and after 6-8 weeks of GnRH agonist-induced gonadal suppression. The test batteries included measures of verbal and spatial memory, spatial ability, verbal fluency, motor speed/dexterity, and attention/concentration. Data were analyzed using repeated-measures models.nnnRESULTSnDuring both eugonadism and hypogonadism, men performed significantly better than women on several measures of visuospatial performance including mental rotation, line orientation, Money Road Map, Porteus maze, and complex figure drawing. Although some test performances showed an effect of hormone treatment, the majority of these differences reflected an improved performance during hypogonadism compared with baseline (and probably reflected practice effects).nnnCONCLUSIONnThe well-documented male advantage in visuospatial performance, which we observed during eugonadal conditions, was maintained in the context of short-term suppression of gonadal function in both men and women. These findings suggest that, in humans, sex differences in visuospatial performance are not merely dependent on differences in the current circulating sex steroid environment. Thus sex differences in visuospatial performance in adulthood could reflect early developmental effects of sex steroid exposure or other environmental exposures differing across the sexes as our data confirm that these differences are independent of circulating estradiol or testosterone levels in men and women.

Mortality Rates Among Substance Use Disorder Participants in Clinical Trials: Pooled Analysis of Twenty-Two Clinical Trials Within the National Drug Abuse Treatment Clinical Trials Network

BACKGROUNDnMost substance use disorders (SUD) treatment clinical trials are too short and small to reliably estimate the incidence of rare events like death.nnnOBJECTIVEnThe aim of this study is to estimate the overall mortality rates among a SUD treatment-seeking population by pooling participants from multiple clinical trials conducted through the National Institute on Drug Abuse (NIDA)-sponsored National Drug Abuse Treatment Clinical Trials Network (CTN).nnnPARTICIPANTSnDrug and or alcohol users (N=9866) who sought treatment and participated in one of the twenty-two CTN trials.nnnMEASUREMENTSnData were collected through randomized clinical trials in national community treatment programs for SUD. Pooled analysis was performed to assess age- and gender-standardized mortality rate(s) (SM rate(s)), and mortality ratio(s) (SM ratio(s)) of CTN trial participants compared to the U.S. general population.nnnRESULTSnThe age- and gender-SM rate among CTN trials participants was 1403 (95% CI: 862-2074) per 100,000 person years (PY) compared to 542 (95% CI: 541-543) per 100,000 PY among the U.S. general population in 2005. By gender, age-adjusted SM ratio for female CTN trial participants was over five times (SM ratio=5.35, 95% CI: 3.31-8.19)), and for male CTN trial participants, it was over three times (SM ratio=3.39, 95% CI: 2.25-4.90) higher than their gender comparable peers in the U.S. general population.nnnCONCLUSIONSnAge and gender-standardized mortality rates and ratios among NIDA CTN SUD treatment-seeking clinical trial participants are higher than the age and gender comparable U.S. general population. The overall mortality rates of CTN trial participants are similar to in-treatment mortality reported in large U.S. and non-U.S. cohorts of opioid users. Future analysis with additional CTN trial participants and risk times will improve the stability of estimates, especially within subgroups based on primary substance of abuse. These SUD mortality rates can be used to facilitate safety monitoring within SUD clinical trials.

Choroid Plexitis and Ependymitis by Magnetic Resonance Imaging are Biomarkers of Neuronal Damage and Inflammation in HIV-negative Cryptococcal Meningoencephalitis

CNS cryptococcal meningoencephalitis in both HIV positive (HIV+) and HIV negative (HIV−) subjects is associated with high morbidity and mortality despite optimal antifungal therapy. We thus conducted a detailed analysis of the MR imaging findings in 45 HIV− and 11 HIV+ patients to identify imaging findings associated with refractory disease. Ventricular abnormalities, namely ependymitis and choroid plexitis were seen in HIV− but not in HIV+ subjects. We then correlated the imaging findings in a subset of HIV− subjects (nu2009=u200917) to CSF levels of neurofilament light chain (NFL), reflective of axonal damage and sCD27, known to best predict the presence of intrathecal T-cell mediated inflammation. We found that ependymitis on brain MRI was the best predictor of higher log(sCD27) levels and choroid plexitis was the best predictor of higher log(NFL) levels. The availability of predictive imaging biomarkers of inflammation and neurological damage in HIV− subjects with CNS cryptococcosis may help gauge disease severity and guide the therapeutic approach in those patients.

Data and Safety Monitoring

Safety and data monitoring is an essential part of clinical trial implementation, and a data and safety monitoring plan is a key component of clinical trial design. This chapter addresses the importance of monitoring during trial conduct and lists some of the key components of the monitoring plan, including what, when and how often to monitor. It discusses the composition, role and responsibilities of the Data and Safety Monitoring Board. It briefly describes the statistical concepts behind sample size recalculation and interim analyses for efficacy and futility, with a brief discussion on when to stop a trial. Additional references that include more in-depth coverage of this topic are provided.

Use of a self-reported psychosocial distress screening tool as a predictor of need for psychosocial intervention in a general medical setting

ABSTRACT This study describes the development of a self-reported psychosocial distress screening tool for a general medical population and criteria to predict the need for psychosocial intervention. The objectives were to develop criteria to determine which patients need in-person screening and establish criteria identifying patients who are more likely to require psychosocial interventions. The outcomes have bearing on reducing initial psychosocial screening workload for medical social workers in high volume medical settings. Furthermore, a criterion for scoring the self-reported tool can predict which patients will need further social work intervention. The results suggest criteria are a score on the adapted Distress Thermometer of five or greater, at least two negative emotions, and a lack of health insurance. The optimal criterion identified 36% (446/1228) of patients in need of in-person screening with the remaining 64% (782/1228) screened low risk through the tool, representing a significant workload reduction.

The role of nitrite in muscle function, susceptibility to contraction injury, and fatigability in sickle cell mice

Sickle cell disease (SCD) patients can have limited exercise capacity and muscle dysfunction characterized by decreased force, atrophy, microvascular abnormalities, fiber distribution changes, and skeletal muscle energetics abnormalities. Growing evidence suggests that in SCD there is alteration in nitric oxide (NO) availability/signaling and that nitrate/nitrite can serve as a NO reservoir and enhance muscle performance. Here, we examined effects of nitrite on muscle strength, exercise capacity, and on contractile properties of fast-(extensor digitorum longus, EDL) and slow-twitch (soleus) muscles in SCD mice. Compared to controls, homozygotes (sickling) had decreased grip strength, impaired wheel running performance, and decreased muscle mass of fast-twitch, but not slow-twitch muscle. Nitrite treatment yielded increases in nitrite plasma levels in controls, heterozygotes, and homozygotes but decreases in muscle nitrite levels in heterozygotes and homozygotes. Regardless of genotype, nitrite yielded increases in grip strength, which were coupled with increases in specific force in EDL, but not in soleus muscle. Further, nitrite increased EDL, but not soleus, fatigability in all genotypes. Conversely, in controls, nitrite decreased, whereas in homozygotes, it increased EDL susceptibility to contraction-induced injury. Interestingly, nitrite yielded no changes in distances ran on the running wheel. These differential effects of nitrite in fast- and slow-twitch muscles suggest that its ergogenic effects would be observed in high-intensity/short exercises as found with grip force increases but no changes on wheel running distances. Further, the differential effects of nitrite in homozygotes and control animals suggests that sickling mice, which have altered NO availability/signaling, handle nitrite differently than do control animals.